FECAPENTAENES MECHANISTIC STUDIES

我们的目的是追求的作用机制的理解， fecapentaenes和哺乳动物系统中的解毒过程。 通过 这种知识，阻止行动和/或加速行动的手段， 这些化合物的失活可以实际地探索， 降低人类患结肠癌的风险。这些目标可以通过以下方式实现： 结合我们在合成有机化学和结构方面的经验， 解析，在分析生物化学和生物化学药理学，和 癌症生物学和生物化学。 Fecapentaenes及其衍生物将被合成为未标记的， 用稳定的放射性同位素标记。 未标记的化合物将 用于致突变和致癌活性的初始试验， 通过大鼠组织制备物（肝，小肠， 和大肠）。 将通过以下两种测定来监测解毒： 致突变性和致癌性的丧失以及使用 液相色谱法 稳定的放射性同位素标记 将在机理研究中使用非卡戊烯， 代谢物。 致癌物质的两种可能的作用机制是 检查：DNA加合物的形成和原癌基因的激活， 哺乳动物细胞

Our purpose is to pursue an understanding of the mechanism of action of the fecapentaenes and of the detoxication processes in mammalian systems. By such knowledge, the means of blocking the action and/or of accelerating the inactivation of these compounds may be realistically explored to ultimately reduce the risk of colon cancer in man. These goals can be best pursued by combining our experiences in synthetic organic chemistry and structure elucidation, in analytical biochemistry and biochemical pharmacology, and in cancer biology and biochemistry. Fecapentaenes and their derivatives will be synthesized both unlabeled and labeled with stable and radioactive isotopes. Unlabeled compounds will be employed in initial assays of mutagenic and carcinogenic activities and studies of detoxication by rat tissue preparations (liver, small intestine, and large intestine). Detoxication will be monitored both by assays for loss of mutagenicity and carcinogenicity and by chemical analyses using liquid chromatography. Stable and radioactive isotopically labeled fecapentaenes will be used in mechanistic studies and to identify metabolites. Two possible mechanisms of action of carcinogens will be examined: DNA-adduct formation and activation of proto-oncogenes in mammalian cells.